Cannula For Minimizing Dilution Of Dosing During Nitric Oxide Delivery

ABSTRACT

Described are nasal cannulas that improve the precision of the delivered dose for nitric oxide therapy by reducing the dilution of nitric oxide. The nasal cannulas may reduce the total volume and potential for retrograde flow during nitric oxide therapy through the design of the specific dimensions of the flow path and/or having check valves in the nitric oxide delivery line and/or having a flapper or umbrella valve dedicated to nitric oxide delivery. The nasal cannulas may also use materials that limit oxygen diffusion through the cannula walls. The nosepiece for these cannulas may be manufactured by a molding technique.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. § 120 of U.S. patentapplication Ser. No. 15/790,300, filed Oct. 23, 2017, which is acontinuation under 35 U.S.C. § 120 of U.S. patent application Ser. No.14/096,548, filed Dec. 4, 2013, now U.S. Pat. No. 9,795,756, whichclaims, under 35 USC § 119(e), the benefit of U.S. ProvisionalApplication No. 61/733,134, filed Dec. 4, 2012 and U.S. ProvisionalApplication No. 61/784,238, filed Mar. 14, 2013, the contents of each ofwhich are hereby incorporated by reference in their entireties.

TECHNICAL FIELD

Embodiments of the present invention generally relate to the field ofmethods and devices for nitric oxide delivery.

BACKGROUND

Nitric oxide (NO) is a gas that, when inhaled, acts to dilate bloodvessels in the lungs, improving oxygenation of the blood and reducingpulmonary hypertension. Because of this, nitric oxide is provided as atherapeutic gas in the inspiratory breathing gases for patients withpulmonary hypertension.

Typically, inhaled NO is delivered in a carrier gas from a high pressuresource (such as a pressurized cylinder) to the patient at or nearambient pressure by means of a respiratory tube for ICU ventilator boundor anesthesia patients or a nasal cannula for spontaneously breathingpatients. It is particularly challenging to deliver an accurate andconsistent dose to the patient through a nasal cannula as dilution ofthe dose can occur through retrograde flow and diffusion of other gases.

Delivery of NO may require transit through a nasal cannula. Duringpatient inhalation and exhalation, a driving pressure gradient can causeretrograde flow in the nasal cannula supply lumen, thereby diluting theNO dose in the cannula with exhaled gas. In addition, diffusion ofambient gasses can occur through the cannula itself during the transittime of NO through the cannula. Oxygen is of specific concern as itreacts with NO to form nitrogen dioxide (NO₂) thereby reducing the NOconcentration. This is further exacerbated by the fact that patients onNO may also require oxygen therapy. Both of these issues can dilute thedelivered dose of NO during inhaled NO therapy.

Accordingly, there is a need for new methods and apparatuses forpreventing dilution of dosing within the delivery conduit of a nitricoxide delivery apparatus.

SUMMARY

Aspects of the present invention relate to improved nasal cannulas thatminimize retrograde flow and permeation of oxygen during NO therapywhile allowing NO delivery to both nares of the nostril. Such cannulasmay reduce dilution of the delivered dose by using cannula materialsthat limit oxygen diffusion through the cannula walls and/or utilizecannula configurations that prevent mixing of co-delivered O₂ and NOand/or reduce retrograde diffusion through the patient end of thecannula. Aspects of the present invention also relate to methods ofminimizing the dilution of the NO dose. Other aspects pertain to methodsof treatment utilizing these nasal cannulas and/or methods ofadministration. Other aspects of the invention relate to methods ofmanufacturing multi-lumen cannulas and their nosepieces.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above recited features of the presentinvention can be understood in detail, a more particular description ofthe invention, briefly summarized above, may be had by reference toembodiments, some of which are illustrated in the appended drawing. Itis to be noted, however, that the appended drawing illustrates onlytypical embodiments of this invention and are therefore not to beconsidered limiting of its scope, for the invention may admit to otherequally effective embodiments.

FIGS. 1A and 1B show the pneumatic paths for the NO, oxygen and triggerlines in a tri-lumen cannula;

FIG. 2 shows three lumina integrated into a single cannula head;

FIG. 3 shows a cross-section of an integrated three-lumina cannula;

FIGS. 4A and 4B show the pneumatic paths for the NO, oxygen and triggerlines in a quad-lumen cannula;

FIG. 5 shows four lumina integrated into a single cannula head;

FIGS. 6A and 6B show details of duck bill check valves;

FIGS. 6C and 6D show details of umbrella check valves;

FIG. 7 shows a nasal cannula with an umbrella or flapper valve fordelivering NO;

FIG. 8 shows retrograde flow during inspiratory breathing along withpulsed delivery;

FIG. 9 shows retrograde flow during both inspiratory and expiratorybreathing;

FIGS. 10A and 10B show cross-flow between two nasal cannula prongs;

FIG. 11 shows a nasal cannula with two lumina of different sizes;

FIGS. 12A and 12B show two embodiments of incorporating a valve into theNO delivery line;

FIG. 13 shows a dual-lumen cannula for co-delivering NO and O₂;

FIG. 14 shows retrograde flow for various cannula configurations;

FIGS. 15A-C show the cannula configurations for Tests 1-3 of FIG. 14;

FIG. 16 shows a nasal cannula with a triple lumen nosepiece;

FIG. 17 shows a molded triple lumen nosepiece prior to assembly;

FIG. 18 shows the nasal prong of the assembled molded triple lumennosepiece; and

FIG. 19 shows a perspective and a two-dimensional representation of anasal prong with a NO lumen proximal to and within a trigger lumen.

DETAILED DESCRIPTION

Methods of delivering inhaled nitric oxide (NO) should ideally beoptimized to ensure accurate and consistent delivery of the dose to thepatient. Typically, NO is delivered at relatively low volumetric percentconcentrations in a carrier gas. Nitrogen is a common carrier gas for NOdelivery because nitrogen is non-reactive with NO, but other inertcarrier gases such as helium may be used. Delivery of the NO/N₂ gasmixture to the patient typically requires that the gas travel from ahigh pressure NO source (such as a pressurized cylinder) to the patientat or near ambient pressure by means of a respiratory tube for ICUventilator bound or anesthesia patients or a nasal cannula forspontaneously breathing patients. This travel of the NO is ideallydevoid of contact with other gasses, such as ambient air, oxygen, carbondioxide, etc., until the gas enters the patient's upper respiratorytract. However, in practice, this is not easily achieved. Specifically,oxygen and ambient air can enter the delivery system at a number ofpoints as follows:

-   -   During the connection of the high pressure source (typically        cylinder) to the delivery device    -   During the NO gas transit through the cannula (by way of        diffusion across the cannula wall)    -   During the inhalation/exhalation cycle when a driving pressure        gradient seeks to reverse flow in the nasal cannula NO supply        lumen producing mixing within the cannula with ambient air

The dilution of NO during pulsed NO therapy may be problematic becauseonly a small volume of NO is delivered to the patient. For example, theNO-containing gas may be administered in pulses less than 1 mL. Withsmall pulse volumes, even small volumes of retrograde flow or diffusedgases may be significant because the NO dose may be diluted.

Materials:

One or more embodiments of the present invention relate to a nasalcannula that addresses one or more of these above sources of oxygen/NOcontact and thereby dilution of the intended NO dose. One particularsource of oxygen that may be minimized is the transit of oxygen acrossthe cannula walls. In one or more embodiments, a cannula is providedthat includes a smaller inside diameter (ID) delivery tube/lumen for NO.This smaller ID tube reduces the transit time of the NO moleculesthrough the cannula, thereby reducing the time available for oxygen todiffuse across the walls of the cannula and oxidize the internal NO intoNO₂.

Another approach to minimize the oxygen contact provided by oxygendiffusion across the cannula walls is to use a wall material thatminimizes the oxygen diffusion rate. Accordingly, in some embodiments,the cannula wall comprises a material with a low oxygen diffusioncoefficient. Polyvinyl chloride (PVC) is currently a common material forconstructing nasal cannulas, but it is not optimal for reducing oxygendiffusion through the cannula walls. Accordingly, some embodimentsprovide using urethane or another similar soft material. In someembodiments, the urethane or other soft material includes an additive toenhance the resistance to oxygen diffusion. Examples of suitableadditives include oxygen resistant polymers such as polyvinylidenechloride (PVDC), ethylene vinyl alcohol (EVOH), polyamide (PA) orsimilar materials. Alternatively, PVC may be used as the cannulamaterial, but one or more additives such as oxygen resistant polymersmay be incorporated to reduce the oxygen diffusion coefficient of thematerial. The oxygen resistant polymers may be incorporated into theurethane or other cannula material through co-extrusion. Such anextrusion may be achieved with a dual head extruder.

Pneumatic Configurations:

Another potential source of nitric oxide dilution is from retrogradeflow in the nasal cannula. Retrograde flow, also known as cross flow, isa phenomenon in which ambient air flows in opposite directions betweenthe two delivery prongs of the nasal cannula. As shown in FIG. 10A,during normal pulsed delivery, NO flows out of both nasal prongs of thecannula. However, during the static phase between pulses, ambient aircan flow in a circular motion in through one prong and out the otherprong as shown in FIG. 10B. The degree of retrograde flow depends on thepressure difference between the nares during both the inhalation andexhalation phase. The pressure difference between the nares can varydepending on the person's breathing pattern, placement of the nasalprongs and the degree of misbalance between the nasal flow duringbreathing. Retrograde flow results in dilution and washout of the NO inthe nasal prongs and flow path. This can cause a delay or reduction inthe delivered dose. Furthermore, air may react with nitric oxide in thenasal cannula, thus forming NO₂ and further diluting the NOconcentration.

Accordingly, aspects of the present invention also provide nasalcannulas that may minimize the retrograde flow in the nasal cannula.Such nasal cannulas may include a means of delivering oxygen andtherapeutic gas containing NO, and may be able to transmit pressuretransients associated with inhalation-based gas flow triggering. If thecannulas deliver oxygen in addition to NO, the oxygen may be provided byan oxygen conserver or an oxygen concentrator.

In one or more embodiments, the nasal cannula has two lumina (i.e. adual-lumen cannula). FIG. 11 shows an exemplary dual-lumen cannula thatdelivers nitric oxide in a separate lumen than is used to deliver oxygenand/or trigger the delivery device. The NO lumen carries therapeutic gascomprising NO from the NO delivery device to the patient. The triggerlumen does not deliver gas to the patient, but instead establishes fluidcommunication between the patient's nares and a trigger sensor in the NOdelivery device. When the patient begins a breath, a drop in pressureoccurs in the nares. This pressure signal is communicated through thetrigger lumen to the trigger sensor, which then senses that the patienthas begun inspiration. The trigger sensor can then send a signal to aCPU in the NO delivery device so that the CPU will open a control valveto deliver NO to the patient, such as a pulse of NO in a carrier gas.

As shown in FIG. 11, in some embodiments the lumen that carries thenitric-oxide containing gas may have a smaller inner diameter than theother lumen such as the triggering lumen. In these embodiments, thecannula may reduce dilution by at least two potential mechanisms: 1) thecannula may minimize mixing of oxygen and NO by two means, first areduction in retrograde flow into the small ID NO carrying lumen due tothe smaller, ID, second the volume of gas per unit length is reducedthereby reducing the bulk volume of gas mixing occurring; and 2) thenarrow ID produces a narrow jet of gas flow which effectively minimizesO₂/NO mixing during NO delivery until much further into the nasalcavity. The diameter of the small lumen may be minimized by engineeringdesign such that it is as small as reasonably possible without producingconfounding upstream effects on the flow delivery mechanics of thedevice. In some embodiments, the ratio of the ID of the NO lumen to theID of the trigger lumen may be 1:1, 1:1.2, 1:1.3, 1:1.5, 1:2, 1:2.5,1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12,1:15, 1:20, 1:25 or 1:30.

Also, the geometry of the nasal cannula lumina may be optimized toprevent retrograde flow. Thus, in addition to circular or paraboliccross-sections, the cross-section of any of the nasal cannula luminadescribed herein may be square, rectangular, triangular or any otherregular or irregular shape to minimize dose dilution. When one or morecross-sectional areas are not circular, then the ratio of innerdiameters may be the square root of the ratio of the surface areas ofthe two lumina sections.

Alternatively, a dual-lumen cannula may have a first lumen for oxygendelivery and a second lumen for delivery of NO and transmitting thepressure signal for the trigger sensor. Such a two lumina configurationis shown in FIG. 13. In this configuration, the first lumen carriesoxygen from the oxygen conserver/concentrator to the nosepiece of thecannula. The second lumen delivers NO from the nitric oxide deliverydevice to the patient and delivers the pressure-based triggering signalfrom the patient to trigger sensor of the nitric oxide delivery device.Both lumina would be constructed to “tee” to both nares and thus be inunobstructed fluid communication with both nares as shown in FIG. 13.

The first lumen for carrying oxygen may be constructed with lumen innerdiameter geometry consistent with industry norms. For instance, nasalcannulas with rated 6 LPM oxygen delivery capacity typically provide anoxygen lumen inner diameter of approximately 0.080″ at or near thenosepiece.

The second lumen of the this dual-lumen cannula may have a geometryunique to the gas delivery objectives of the nitric oxide deliverysystem. Nitric oxide delivery systems which pulse nitric oxide gas intothe patient are believed to have optimal clinical efficacy when a pulseor flow of nitric oxide is delivered to the patient as early in theinspiratory phase as possible. Therefore, any pneumatic delays would notbe optimal. Further, the shape of the flow waveform as delivered by thenitric oxide delivery system is, optimally, not distorted during transitfrom the device to the patient. In addition, the transit of the pressuresignal from the patient indicative of inspiratory effort preferably isnot delayed/distorted when in transit from the patient back to thedevice. Finally, the volume of potential nitric oxide mixing with eitherexhaled gas or ambient gas is preferably minimized to reduce thepotential for oxidation of nitric oxide at the nosepiece of the cannula,which again can produce NO₂ which dilutes the NO dose and is a knownrespiratory irritant.

In order to achieve the goals described above for the second lumen,there are several competing metrics of lumen ID optimization as notedbelow:

-   -   a. Reduce NO₂ formation->Reduce lumen ID    -   b. Maintain volumetric NO dosing accuracy->Reduce lumen ID    -   c. Reduce NO flow distortion->Lumen ID within certain bounds    -   d. Minimize trigger signal attenuation or delay->Increase lumen        ID

Therefore, an optimal inner diameter dimension of the second lumen wouldaddress all of these concerns to ensure adequate device performance.Such optimal ID dimensions may vary depending on the volume ofNO-containing gas delivered by the nitric oxide delivery device. Forexample, a nitric oxide delivery device may deliver pulses ofNO-containing gas with a minimum dose volume of 0.35 mL. In order toensure volumetric dosing accuracy, it is preferable that no more than10% of the dose can be lost due to ambient bleed of NO in betweeninspiratory efforts. Such a bleed can occur during the exhalation phasein which imbalances in the flow out of the nostrils results in a “highflow nostril” and a “low flow nostril.” Flow into the prong from thehigh flow nostril may result in flow of out of (gas loss out of) theprong of the low flow nostril. This gas, which is located in the “U”shaped portion of the tee′d lumen, is lost to ambient during theexhalation phase and would consist of NO therapeutic gas. Therefore, oneor more embodiments of the present invention limit the internal volumeof this “U” shape to be no more than 10% of the minimum dose volume(i.e. 0.035 mL for a 0.35 mL pulse of therapeutic gas), thus ensuringacceptable NO loss to ambient during the exhalation phase. Such arequirement of 0.035 mL requires a lumen ID within the “U” segment of nomore than 0.046″ given a prong length of 8 mm and a prong spacing of 16mm. Therefore, a lumen ID significantly larger than 0.046″ would not beadvantageous to maintaining dose volume accuracy for minimum dosevolumes of 0.35 mL. Of course, it is understood that the mathematics ofthis construct would be modified by systems with larger or smallerminimum dose volumes appropriately, or with different prong lengthsand/or prong spacing. One skilled in the art can perform the requiredcalculations to determine the ID required to provide a desired volume inthe “U” section so that it does not exceed 10% of the dose volume.Furthermore, depending on the required accuracy for the dosing, theinternal “U” volume or other volume available for cross-flow may be lessthan 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1%of the dose volume.

In addition to the volumetric dosing accuracy concern, another concernis that the second lumen ID not produce gas flow distortion. However,given that gas flow in a nitric oxide system may use restrictors whichare significantly smaller in inner diameter than a NO lumen ID of 0.046inches, such distortion may not actually occur.

Finally, the inner diameter of the second lumen preferably does notproduce undue signal propagation delay from the patient to the device.Such delay is believed to occur as pneumatic tubes behave as first orderpneumatic low pass filters and attenuate higher bandwidth signalcomponents. Modification of the inner diameters is known to change theband pass characteristics of the filtering effect. However, as notedearlier, the inner diameter (at the U) may be fixed to a certain maximumID based on the required dose delivery accuracy of the system.Therefore, in order to minimize the effects of the potentially frequencyattenuated pressure signal, two measures can be taken. First theupstream (close to device) diameter of the second lumen may be adjustedto widen (optimize) the band pass characteristics of the cannula. Thismay ensure that unneeded compressible volume is unavailable upstream ofthe nose piece restriction (0.046″ ID restriction). This reduces thecompressible volume in the cannula and effectively increases thebandpass characteristics of the cannula. The second measure which can betaken is to trigger the initiation of pulse delivery on the device notbased on a threshold pressure level (the magnitude of which can whichcan be delayed by frequency attenuation) but by triggering the devicebased on a pattern of sloping pressure indicative of patient effort.Such a slope may be reduced in magnitude by the filteringcharacteristics of the tubing, however, the slope will still be presentfor algorithmic triggering decisions by the device. However, such atriggering implementation is optional.

Accordingly, in some embodiments, the dual lumen cannula would have anoxygen lumen in the range from 0.05 to 0.12″ ID (such as about 0.080″ID) which tees at the nosepiece and is in fluid communication with bothnares. It would also have a second (nitric oxide) lumen (similarly influid communication with both nares) with an internal tubing diameterdictated by volumetric dosing accuracy considerations and the secondlumen may have an ID in the range from 0.01 to 0.08″ (such as about0.046″ ID) with upstream tubing adjusted to optimize the bandpassperformance of the system. Finally, device triggering methodologiesbased not on pressure thresholds, but based on pressure slope trends canalso be employed to improve overall timely delivery of dosing to thepatient.

Other pneumatic configurations for the nasal cannula may utilizedifferent numbers of lumina. In one or more embodiments, the nasalcannula has three lumina (i.e. a tri-lumen cannula). FIG. 1A shows anexemplary set of pneumatic paths of the three individual lumen from anitric oxide delivery device to the patient. The three lumina mayinclude a NO lumen, a trigger sensor lumen and an oxygen lumen. Theoxygen lumen carries an oxygen-enriched gas (such as oxygen-enriched airor substantially pure oxygen) from an oxygen source to the patient. Theoxygen source may be a typical oxygen pulsing device, or may be a porton the NO delivery device that delivers the oxygen-enriched gas. FIG. 1Bshows the three lumina aggregated into a single cannula. In FIGS. 1A and1B, the NO lumen is tee′d at some point between the patient and the NOdelivery device. Further, the oxygen and trigger lumina are also tee′dat some point between the device and the patient and might be tee′d intwo locations, such as having an additional tee in the cannula head atthe two nasal prongs.

Again, all three of the lumina may be integrated into a single cannula.FIG. 2 shows one such method for integration of the three lumina at thehead (nose bridge fitting) of the cannula. The separation of thepneumatic paths or lumina in FIG. 2 is by means of partitions ordiaphragms within the head and prongs of the cannula. The NO supplytraverses to the head through a lower gas resistance source to higherresistance orifices integrated into the prongs of the cannula. Alllumina are separated by a diaphragm partition within the head of thecannula and within the prongs of the cannula, which prevents mixing ofthe fluid streams in the separate lumina.

The tubes of the cannula carry backwards towards the patient and may beaffixed to each other so as to produce a clean single element umbilicalbetween the cannula head and the device as shown in FIG. 3, whichprovides a cross-section. Alternately, the three lumina can be extrudedthrough a single die producing a multi-lumen tube.

As can be seen from FIG. 2, the NO delivery tube may decrease in innerdiameter (ID) once the tubing enters the head of the nasal cannula.Accordingly, in one or more embodiments, the pneumatic resistance isgreater in the prongs of the nasal cannula than in the tubing carryingthe NO from the NO delivery device to the cannula head. Such a devicemay have many advantages. In some embodiments, the smaller ID tubing ofthe dedicated NO delivery lumen will allow for:

-   -   Short gas transit times    -   Reduced inspiratory/expiratory phase retrograde flow of ambient        air into the lumen (reduced according to Knudsen diffusion which        states that diffusion rate is proportionate to the mean free        path length of the gas molecule which is reduced with smaller        ID)    -   Increased gas resistance to flow (smaller ID tubing produces gas        flow resistance which is inversely proportional to the fourth        power of tubing radius by Poiseuille's Law).    -   Reduced volume in the tee′d loop of the NO delivery lumen

All of the above may serve to reduce the potential for retrograde flowand/or reduce the volume of retrograde flow and/or reduce the contact orcontact duration between NO and other gasses including oxygen in thecannula. This will reduce the dilution of NO and thereby increase theprecision of the delivered NO dose.

The ID of the NO lumen may decrease from a maximum ID to a minimum ID.In some embodiments, the ratio of the minimum ID to the maximum ID ofthe NO lumen may be 1:1, 1:1.2, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5,1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7, 1:8, 1:9 or 1:10.

The trigger lumen ID may be comparatively much larger than the NO lumenID. Trigger pressure drop on inhalation must be transmitted through thiscannula lumen with the smallest possible loss of signal magnitude to theNO delivery device which in turn uses this pressure signal to deliverpulsed NO. Again, in some embodiments, the ratio of the ID of the NOlumen to the ID of trigger lumen may be 1:1, 1:1.2, 1:1.3, 1:1.5, 1:2,1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7, 1:8, 1:9, 1:10,1:12, 1:15, 1:20, 1:25 or 1:30.

The oxygen lumen may also be larger than the NO lumen to minimize oxygenflow resistance and to reduce gas flow speed at the prongs which couldserve to interfere with the triggering pressure signal due to gas floweffects such from Bernoulli's principle. As with the trigger lumen, insome embodiments the ratio of the ID of the NO lumen to the ID of theoxygen lumen may be 1:1, 1:1.2, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5,1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25or 1:30.

Another pneumatic configuration is shown in FIGS. 4A and 4B. Like thepneumatic configurations shown in FIGS. 1A and 1B, this configurationseparates the pneumatic paths of the NO, oxygen and trigger. However,unlike the configuration shown in FIGS. 1A and 1B, in the configurationshown in FIGS. 4A and 4B, the NO flow delivery paths to each nostril arekept separate and distinct and have their own pneumatic delivery sourceat the NO delivery device. Accordingly, this configuration has fourlumina (i.e. a quad-lumen cannula).

One potential benefit of the quad-lumen approach is to prevent movementof gas through the tee′d delivery loop of the NO supply line duringexhalation. This may reduce NO/oxygen contact. However, unlike thetri-lumen cannula, use of the quad-lumen cannula may require dedicatedpneumatic circuitry for each NO lumen.

FIG. 5 shows one potential method for achieving this configuration atthe cannula head. As with the tri-lumen cannula, the quad-lumen cannulafuses the lumen of the cannula into a single umbilical between thecannula head and the device.

With any of the pneumatic configurations described herein, there may beother modifications of the cannula to improve NO dosing. In one or moreembodiments, provided is a nasal cannula with one or more check valvesin the nitric oxide delivery line. This configuration may be combinedwith one of the multi-lumen configurations described above. The checkvalves(s) help to prevent retrograde gas movement into the NO supplylumen during inhalation/exhalation. Such a check valve might consist ofany low cracking pressure check valve which is placed at some point inthe NO delivery path. Such check valves may include, but are not limitedto, duckbill valves or umbrella valves. Exemplary duck bill valves areshown in FIGS. 6A and 6B and exemplary umbrella valves are shown inFIGS. 6C and 6D. These check valves may be miniature check valves so tohave the proper dimensions to fit in the NO delivery lumen.

In one or more embodiments, provided is an NO delivery cannula having asmall flapper or umbrella check valve at the head of the cannulaallowing pulses of NO to be delivered to the general nose/mouth areaduring device NO pulsing. An exemplary configuration of a nasal cannulawith such a flapper or umbrella valve is shown in FIG. 7. Thisconfiguration would allow NO to flow into either/both open nares uponinhalation. The O₂ and trigger lumen may be combined (as shown in FIG.7) or kept separate to improve the signal-to-noise performance of thetrigger lumen. Such a configuration with the flapper valve would preventretrograde flow of oxygen into the NO delivery path thereby reducing thepotential for dilution of the dose. A diaphragm or other barrierseparates the NO delivery line from the O₂/trigger line at the cannulahead to prevent mixing.

This pneumatic configuration may be combined with any of the otherpneumatic configurations described above.

In one or more embodiments, also provided is a nasal cannulaincorporating an impermeable or semi-permeable membrane. The membranemay be movable or fixed but can be actively or passively moved whenneeded, that separates the NO containing gas or material from the O₂containing gas or material until the NO needs to be delivered to thepatient. This membrane may reduce one or more of the contact time,surface area and diffusion rate between the NO and O₂ containing gases.This may reduce the formation of NO₂, which dilutes the intended NOdelivery concentration.

In some embodiments of the membrane, a normally-closed valve at the tipof the NO containing cannula prevents air from contacting the NOcontaining gas inside the cannula until the valve opening is triggered(e.g. by a drop in pressure caused by inhalation by the patient or bythe positive pressure caused by the delivery device as it attempts todeliver the NO containing gas to the patient). When the valve opening istriggered, the NO is then delivered to the patient. One embodiment ofsuch a valve is shown in FIG. 12A.

In one or more embodiments, also provided is a system to expel the gasor other NO containing material that does come in contact with O₂containing gas or material, which may have otherwise formed NO₂ in thismixture. The system may subsequently allow another part of the NOcontaining gas or material that has minimal or no NO₂ to be delivered tothe patient Again, this NO₂ formation could serve to dilute the NO dosebefore delivery to the patient.

In some embodiments of this system, this system may comprise anelectromechanical valve system that actuates to pump out a fixed oradjustable amount of gas mixture that might contain NO₂ through aseparate orifice than the cannula opening to the patient. The system maythen actuate to pump the NO containing gas or material to the patient.One embodiment of such a system is shown as a 3-way valve in FIG. 12B.

The membrane and/or valve system may be combined with any of the otherpneumatic configurations described above.

Manufacturing of Multi-Lumen Nasal Cannulas

As described above, the individual lumen of a multi-lumen cannula may beseparately manufactured and then affixed to each other, or the multiplelumina can be extruded through a single die producing a multi-lumentube.

According to one or more embodiments, the multi-lumen nosepiece of themulti-lumen cannulas described herein may be manufactured by thefollowing molding technique. For example, the cannula may have a triplelumen cannula nosepiece for separate oxygen, nitric oxide and triggeringlumina. In one or more embodiments, the design of the nosepiece for thetriple lumen cannula involves three lumens, two with inner diameters ofapproximately 0.080″ (for oxygen and triggering) and one with a smallerinner diameter of approximately 0.045″ (for nitric oxide) as shown inFIG. 16. However, this configuration may not be readily molded bytypical injection molding techniques as the small lumen would require aninjector pin (of outer diameter 0.045″) which is too small to be robustin a molding tool designed to last for many uses, such as a million ormore shots.

Accordingly, one approach to manufacture the multi-lumen cannulanosepiece is to mold two halves in urethane, PVC, silicone or other lowdurometer elastomer with the internals of the large lumen defined bylarger injector pins (outer diameter 0.080″) and with small half lumenindents defining the outline of the small lumen. These two halves wouldthen be folded and bonded together, preferably with a bonding techniquewhich does not produce residue or flash such as RF welding, to form awhole nosepiece. FIG. 17 shows one embodiment to circumvent the injectorpin limitation with the small ID lumen being defined by indents in thehalves, the two halves would be molded flat in one shot with a webbingholding the halves together and providing gross alignment during thefolding and bonding process. Optionally, the molded halves may compriseintegral holes and mating cylindrical tabs or other complementarymembers so that the halves will be properly aligned when they are foldedtogether. The webbing may also be optional if appropriate complementaryindexing members on the two halves ensure that the two portions formingthe outer wall of the NO lumen will be properly aligned. The assemblednosepiece allows for three lumen inputs and tee's each lumen inputwithin the internals of the nosepiece proper. FIG. 18 shows aperspective view of the nasal prong of the multi-lumen cannula nosepieceof FIG. 17 after the two halves have been assembled.

Again, the lumen ID may be adjusted as described in the previoussections. For example, the ID of the oxygen lumen may range from 0.05 to0.12″, the ID of the trigger lumen may range from 0.05 to 0.12″, and theID of the NO lumen may range from 0.01 to 0.08″. In some embodiments,the IDs of the oxygen lumen and the trigger lumen may both be in therange from 0.07″ to 0.09″ (such as about 0.08″) and the ID of the NOlumen may be in the range from 0.035 to 0.055″ (such as about 0.045″).

An alternate embodiment shown in FIG. 19 involves ensuring that thesmall NO lumen exits proximal to and within the larger trigger lumen.This embodiment ensures that any tip blockage of the larger triggerlumen (for which there is not a purge capability) would be blown out bythe function of the NO pulse. The geometry of this embodiment must becarefully modeled to ensure that all NO in the larger trigger lumenreaches the respiratory system during inspiration and is not left behindto be swept out during exhalation.

Methods of Treatment

Any of the nasal cannulas described herein may be used in nitric oxidetherapy to treat appropriate diseases. For example, the cannulas may befor pulsed NO therapy to treat chronic obstructive pulmonary disease(COPD) or pulmonary arterial hypertension (PAH). For these diseases, thedelivery of the appropriate dose amounts and appropriate dose timing maybe very important. For COPD, the NO may need to be pulsed early ininspiration, such as the first half of inspiration. If NO is notdelivered in the right amount or at the right time, reversal of hypoxicvasoconstriction may occur, which would worsen the patient's condition.Furthermore, the dose amount may be very important for PAH becausesudden discontinuation of therapy can lead to serious events such asrebound hypertension. Thus, significant dilution of the NO dose shouldbe minimized for these diseases. Any of the cannula materials,configurations or methods described herein may be used to minimizedilution of the NO dose during NO therapy.

EXAMPLES

FIG. 8 shows an example of retrograde flow during inspiratory breathalong with pulsed delivery. FIG. 9 shows an example of retrograde flowduring both inspiratory and expiratory breath.

The retrograde flow for various nasal cannula configurations was tested.Typical nasal cannulas that deliver to both nares result in significantretrograde flow as shown in Test 1 of FIG. 14. The nasal cannulaconfiguration of Test 1 is shown in FIG. 15A. For Test 2, theinterconnect between the two prongs was occluded to increase thedistance between the prongs to approximately 19 inches in the hopes thatwould eliminate the retrograde flow. The nasal cannula configuration ofTest 2 is shown in FIG. 15B. As shown in Test 2 of FIG. 14, while thetotal volume of retrograde flow could be reduced, it was not eliminated.Further occluding the pathway with a 7 foot distance between the prongs,as shown in FIG. 15C, had minimal further impact, as shown in Test 3 ofFIG. 14. Surprisingly, it was found that the only way tested thatcompletely eliminated the retrograde flow was when separate circuitswere used for the NO delivery to each nare.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments” or “an embodiment” means that aparticular feature, structure, material, or characteristic described inconnection with the embodiment is included in at least one embodiment ofthe invention. Thus, the appearances of the phrases such as “in one ormore embodiments,” “in certain embodiments,” “in one embodiment” or “inan embodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, structures, materials, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

1.-20. (canceled)
 21. A method of administering nitric oxide fortreating pulmonary hypertension, the method comprising: administering apulse of a gas comprising nitric oxide to a patient in need thereof,wherein the pulse is administered through a nasal cannula comprising acannula nosepiece comprising a nitric oxide flow path having a volumethat is less than 50% of a volume of pulse of the gas comprising nitricoxide.
 22. The method of claim 21, wherein the nasal cannula comprises:a first lumen, a second lumen, and a third lumen: the first lumen beinga first therapeutic gas lumen for delivering the gas comprising nitricoxide to the patient, the second lumen being a triggering lumen, and thethird lumen being a second therapeutic gas lumen for delivering a gascomprising oxygen to the patient; and wherein the cannula nosepiece hasseparate flow paths to the patient for each of (i) the first therapeuticgas lumen, (ii) the triggering lumen, and (iii) the second therapeuticgas lumen.
 23. The method of claim 21, wherein the nasal cannulacomprises a first lumen for delivering the gas comprising nitric oxideto the patient and a second lumen, wherein the first lumen has a smallerinner diameter than an inner diameter of the second lumen.
 24. Themethod of claim 21, wherein the pulse of gas comprising nitric oxide hasa volume less than 1 mL.
 25. The method of claim 21, wherein the nitricoxide flow path is less than 40% of the volume of pulse of the gascomprising nitric oxide.
 26. The method of claim 21, wherein the nitricoxide flow path has a volume less than or equal to 0.035 mL.
 27. Themethod of claim 21, wherein the nasal cannula at least one of inhibitsmixing of nitric oxide and oxygen in the cannula nosepiece and reducesdelivery of nitrogen dioxide to the patient.
 28. A method ofadministering nitric oxide for treating pulmonary hypertension, themethod comprising: administering a plurality of pulses of a gascomprising nitric oxide to a patient in need thereof, wherein theplurality of pulses is administered through a nasal cannula comprising acannula nosepiece comprising a nitric oxide flow path having a volumethat is less than 50% of a volume of each of the plurality of pulses ofthe gas comprising nitric oxide.
 29. The method of claim 28, wherein thenasal cannula comprises: a first lumen, a second lumen, and a thirdlumen: the first lumen being a first therapeutic gas lumen fordelivering a gas comprising nitric oxide to the patient, the secondlumen being a triggering lumen, and the third lumen being a secondtherapeutic gas lumen for delivering a gas comprising oxygen to thepatient; and wherein the cannula nosepiece has separate flow paths tothe patient for each of (i) the first therapeutic gas lumen, (ii) thetriggering lumen, and (iii) the second therapeutic gas lumen.
 30. Themethod of claim 28, wherein the nasal cannula comprises a first lumenfor delivering the gas comprising nitric oxide to the patient and asecond lumen, wherein the first lumen has a smaller inner diameter thanan inner diameter of the second lumen.
 31. The method of claim 28,wherein each of the plurality of pulses of the gas comprising nitricoxide has a volume less than 1 mL.
 32. The method of claim 28, whereinthe nitric oxide flow path is less than 40% of the volume of each of theplurality of pulses of the gas comprising nitric oxide.
 33. The methodof claim 28, wherein the nitric oxide flow path has a volume less thanor equal to 0.035 mL.
 34. The method of claim 28, wherein the nasalcannula at least one of inhibits mixing of nitric oxide and oxygen inthe cannula nosepiece and reduces delivery of nitrogen dioxide to thepatient.
 35. A method of administering nitric oxide to a patient, themethod comprising: administering a plurality of pulses of a gascomprising nitric oxide to the patient, wherein the plurality of pulsesis administered through a nasal cannula comprising a cannula nosepiececomprising a nitric oxide flow path having a volume that is less than50% of a volume of each of the plurality of pulses of the gas comprisingnitric oxide.
 36. The method of claim 35, wherein the nasal cannulacomprises: a first lumen, a second lumen, and a third lumen: the firstlumen being a first therapeutic gas lumen for delivering a gascomprising nitric oxide to the patient, the second lumen being atriggering lumen, and the third lumen being a second therapeutic gaslumen for delivering a gas comprising oxygen to the patient; and whereinthe cannula nosepiece has separate flow paths to the patient for each of(i) the first therapeutic gas lumen, (ii) the triggering lumen, and(iii) the second therapeutic gas lumen.
 37. The method of claim 35,wherein the nasal cannula comprises a first lumen for delivering the gascomprising nitric oxide to the patient and a second lumen, wherein thefirst lumen has a smaller inner diameter than an inner diameter of thesecond lumen.
 38. The method of claim 35, wherein each of the pluralityof pulses of the gas comprising nitric oxide has a volume less than 1mL.
 39. The method of claim 35, wherein the nitric oxide flow path isless than 40% of the volume of each of the plurality of pulses of thegas comprising nitric oxide.
 40. The method of claim 35, wherein thenasal cannula at least one of inhibits mixing of nitric oxide and oxygenin the cannula nosepiece and reduces delivery of nitrogen dioxide to thepatient.